Prostate Cancer May Be Predicted 10 Years Before Diagnosis
with Repeated Measures of Free to Total PSA

Repeated measures of the ratio of free to total prostate specific
antigen (PSA) in a man’s blood can predict a diagnosis of prostate cancer up
to six years earlier than current prediction methods. This discovery by
researchers at the National Institute on Aging (NIA) and colleagues at the
Johns Hopkins University School of Medicine is published in the December,
1996, journal, Urology.

PSA, an enzyme produced by the prostate gland, is found in high
concentration in semen where it acts to liquefy the seminal fluid after
ejaculation so that sperm can swim freely. Some PSA leaks into the blood
stream from prostatic cells, more so when the prostate enlarges. Part of
the PSA binds to alpha-1 antichymotrypsin (ACT), a protein that prevents PSA
from destroying cells by deactivating enzymatic function. Free PSA (the
unbound form of PSA) is active in the semen, and becomes inactive when it
spills into the blood. Free and bound PSA make up total PSA in serum.

Men whose total PSA levels are high may have prostate cancer or benign
prostatic hypertrophy (BPH), an enlarged prostate gland. Earlier studies
have found that the rate of increase in total PSA levels over several years
is one of the best indicators of whether prostate cancer is present.

“Currently, most physicians test for total PSA only, which, when
measured repeatedly over time, can predict prostate cancer up to four years
before clinical diagnosis,” says Dr. James L. Fozard, Associate Scientific
Director for the Baltimore Longitudinal Study on Aging (BLSA) at the National Institute on Aging (NIA), one of the
study’s authors. “This study, however, shows that measuring the ratio of
free to total PSA repeatedly over time may lead to a prediction of prostate
cancer up to 10 years before clinical diagnosis of prostate cancer.”

The NIA and Hopkins team measured free and total PSA levels on stored,
frozen sera from 26 men with no history of prostate disease (control), 29
men with BPH, and 23 men with prostate cancer. All men in this study are
participants in the BLSA, a longitudinal study of aging established in 1958.
They return for follow-up visits every 2 years when they undergo a battery
of tests including collection of blood samples.

Four years before diagnosis, total PSA was significantly greater for
men who developed prostate cancer (5.0ng/ml±0.9) compared to men with BPH
(2.8ng/ml±0.3) and controls (0.8 ng/ml±0.1.) Free PSA levels were similar
among groups at four years before diagnosis. However, the ratio of free to
total PSA continuously decreased among cancer cases over the decade before
prostate cancer diagnosis. At a time when total and free PSA levels were
similar among groups (8 years before diagnosis), the ratio of free to total
PSA was significantly lower for cancer cases (0.13±0.01) compared to BPH
(0.17±0.01) and control cases (0.21±0.02). The values that most accurately
detected prostate cancer were free to total PSA ratio of £0.12 when total
PSA was between 4.0 - 10.0ng/ml.

"The majority of men who have elevated PSA levels and have further
diagnostic tests, such as prostate biopsies, do not have prostate cancer,"
says Dr. H. Ballentine Carter, a urologist at Johns Hopkins School of
Medicine who worked on the study. Dr. Fozard adds, "This study shows that
the ratio of free to total PSA may be useful in helping the physician to
perdict whether prostate cancer is--or is not--developing."

The American Cancer Society, the American Urological Society, and the
American College of Radiology recommend that men have a PSA test and digital
rectal exam annually, beginning at age 50. African American men and those
with a family history of prostate cancer should have the same tests
beginning at age 40.

In 1996, an estimated 317,100 new cases of prostate cancer were
diagnosed, and prostate cancer was responsible for an estimated 41,400
deaths. Prostate cancer rates are 37 percent higher for black men than
white men. Between 1980 and 1990 prostate cancer incidence rates increased
65 percent, largely due to improved detection.

Scientists who worked on this study include: Dr. Jay D. Pearson, Merck
Research Laboratories; Drs. H. Ballentine Carter, Daniel W. Chan, and Alan
W. Partin, The Johns Hopkins University School of Medicine; Drs. James L.
Fozard and E. Jeffrey Metter, the National Institute on Aging; and Dr.
Albert A. Luderer, Dianon Systems, Inc.

The National Institute on Aging, a component of the National Institutes
of Health, conducts and supports biomedical, social, and behavioral research
related to the aging process, age-associated diseases, and the special needs
of older people.